China's original third-generation EGFR-TKI in the treatment of lung cancer highlights its unlimited potential

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) drugs have completely changed the treatment pattern of advanced non-small cell lung cancer (NSCLC) with EGFR sensitive mutations, and the survival time (OS) of patients has also been significantly prolonged The median OS has been extended from about 12 months in the chemotherapy era to 38.
6 months in the third-generation EGFR-TKI era, making this type of advanced lung cancer gradually become a controllable chronic disease
.

However, with the prolonged survival time of patients with advanced lung cancer, some uncommon problems in the chemotherapy era have become more prominent, such as lung cancer brain metastasis and the long-term safety and tolerability of drugs
.

The incidence of central nervous system (CNS) metastasis in advanced NSCLC patients is 40%-50%1, and the survival prognosis is poor, which is one of the common reasons for the failure of lung cancer treatment
.

The third-generation EGFR-TKI can penetrate the blood-brain barrier, so it shows a higher CNS objective response rate (ORR) for the NSCLC population with brain metastasis2,3
.

Compared with the first-generation EGFR-TKI, the third-generation EGFR-TKI can penetrate the blood-brain barrier and enter the brain better
.

However, in clinical practice, treating brain metastases or meningeal metastases is like treating rare or rare EGFR mutations.
It is often necessary to increase the dose of targeted drugs to ensure sufficient drug concentration in the cerebrospinal fluid and brain
.

However, whether the dose can be increased is closely related to the safety and tolerability of the drug
.

Vometinib mesylate (trade name "Ivesa", hereinafter referred to as "Vormetinib") is the third-generation EGFR-TKI drug originally developed in China and was approved for domestic use in March this year.
It is used for the treatment of adult patients with locally advanced or metastatic NSCLC who have experienced disease progression during or after treatment with EGFR TKI and confirmed to be EGFR T790M mutation-positive.
The recommended daily dose is 80 mg
.

Vometinib mesylate was approved in March this year for the treatment of advanced lung cancer.
Vometinib innovatively introduced the trifluoroethoxypyridine structure, so that its prototype drug and its main metabolites have anti-tumor activity and high activity, and both It can "into the brain", and the anti-tumor effects of both have a high degree of selectivity, laying a safe foundation for clinical application
.

Volumetinib and its metabolite AST5902 "double into the brain", and are highly selective The results of the phase I-II clinical study of vometinib announced at the 2020 World Lung Cancer Congress found that a daily dose of 160mg of voumetin The intracranial ORR of patients with brain metastases treated by tinib reached 84.
6%, and the progression-free survival (PFS) reached 19.
3 months, which was relatively better than the 80mg dose4
.

160mg of vomitinib in the treatment of lung cancer brain metastases has a higher intracranial ORR4.
In terms of safety, the results of a phase I-II dose escalation and dose expansion clinical study of vomitinib published in the Journal of Thoracic Oncology in 2020 show that voltinib Compared with the conventional dose group, the metinib high-dose group did not significantly increase adverse reactions (AE), and the incidence of grade ≥3 AE in the 160mg and 240mg dose groups did not exceed 10%5
.

At the just-concluded European Medical Oncology (ESMO) Annual Conference (September 16-September 21), the Phase Ib clinical study of vomitinib in the treatment of EGFR20 exon insertion (ex20 ins) advanced NSCLC (FAVOUR) ) Announce the results of the first-line treatment cohort (Abstract #1325)6
.

 This cohort used three times the usual recommended dose of vomitinib (240mg).
The effective rate as assessed by IRC reached 60%, and the disease control rate was 100%.
Although the dose was high, no grade 3 or above was observed.
No drug reduction or drug discontinuation due to AEs has been observed6
.

Safety data of 240mg vomitinib in the first-line treatment of EGFR 20ins mutant NSCLC 6 At present, there are 3 third-generation EGFR-TKI drugs used in the treatment of lung cancer in China.
The clinical data for the treatment of EGFR mutant lung cancer are generally similar, and they have certain effects on brain metastases.
Curative effect
.

However, in the clinical practice of lung cancer treatment in the real world, some patients require higher doses, which puts forward higher requirements for safety.
If the treatment cannot be tolerated, treatment interruption, dose reduction, discontinuation, etc.
may occur; And the medication is taken without interruption, the longer the medication time, the better the treatment effect will naturally be brought
.

With the use of third-generation EGFR-TKIs in the adjuvant treatment of lung cancer at an earlier stage (stage II-IIIA), the importance of the safety and tolerability of these drugs has become more prominent
.

The drug adjuvant treatment of early and mid-stage lung cancer after R0 resection is basically an intervention without obvious tumor burden.
It is a preventive treatment.
The course of treatment is generally longer than that of advanced lung cancer.
Therefore, The requirements for safety are higher than those of advanced lung cancer, which cannot be operated on but can only receive palliative medical treatment
.

Although based on the results of large-scale phase III clinical studies around the world, China's drug approval and regulatory authorities have approved the third-generation EGFR-TKI for postoperative adjuvant treatment of patients with stage IB-IIIA NSCLC
.

However, there are differences between East and West lung cancer populations.
This is an indisputable fact.
At present, there is still a lack of large-sample evidence-based medicine evidence of the efficacy and safety of third-generation EGFR-TKIs for adjuvant treatment in the Chinese population.
This is crucial for guiding clinical practice in China.
Important
.

The randomized, double-blind, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, randomized, double-blind, developed by He Jianxing, Dean of the First Affiliated Hospital of Guangzhou Medical University, for the adjuvant treatment of EGFR mutation-positive stage II-IIIA NSCLC patients after radical resection with or without adjuvant chemotherapy.
The placebo-controlled, multi-center Phase III registered clinical study (FORWARD) was launched in April this year
.

The study compared the efficacy and safety of vomitinib and placebo in adjuvant treatment for 3 years
.

In the era when lung cancer has become a chronic disease, whether the safety and tolerability of the treatment of mutated EGFR brought about by the high selectivity of vometinib and its metabolites in the Chinese population can be susceptible to advanced EGFR mutations, as well as rare and rare Find a "useful place" in the treatment of mutant NSCLC? Can it play a more important role in the adjuvant treatment of early and mid-term NSCLC? The fixed width and height background can be set on the fixed layout toolbar.
It can be set to be included.
You can perfectly align the background image and text and make your own templates.
On September 25, during the upcoming 24th CSCO conference, many people in the domestic lung cancer treatment industry The coffee will gather at the Vometinib Satellite Conference to show the latest clinical research results of vometinib in the treatment of lung cancer in China, while at the same time exploring its clinical application value, and to explore and examine the effect of the third-generation EGFR-TKI in the treatment of lung cancer in the era of chronic lung cancer.
The new and higher requirements put forward by clinical practice
.

The chairman of the conference will be Professor Zhou Caicun, Department of Oncology, Shanghai Pulmonary Hospital Affiliated to Tongji University, Professor Cheng Ying, Dean of Jilin Cancer Hospital, Professor Shi Yuankai, Deputy Dean of Cancer Hospital Affiliated to Chinese Academy of Medical Sciences, Professor He Jianxing, Dean of First Affiliated Hospital of Guangzhou Medical University, Professor Feng Jifeng, Secretary of the Party Committee of Jiangsu Cancer Hospital/Nanjing Medical University Affiliated Cancer Hospital, and Professor Lu You from the Department of Thoracic Oncology, West China Hospital of Sichuan University, are co-chairing the team
.

Professor Han Baohui from Department of Respiratory Medicine, Shanghai Jiaotong University Chest Hospital, will give keynote speeches with Professor Hu Jian, Director of Pulmonary Disease Diagnosis and Treatment Center of the First Affiliated Hospital of Zhejiang University School of Medicine, and Professor Dong Xiaorong, Department of Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
.

References: 1.
Peters S, et al.
The impact of brain metastasis on quality of life resource utilization and survival in patients with non-small-cell lung cancer, Cancer Treatment Reviews.
2016;45:139-162.
2.
Wu YL, Ahn MJ, Garassino MC, et al.
CNS efficacy of osimertinib in patients with T790M-positive advanced non-smallcell lung cancer: data from a randomized phase III trial (AURA3).
J Clin Oncol 2018; 36: 2702-9.
3.
Yuankai Shi , Xingsheng Hu,Shucai Zhang, et al.
Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase Ⅱb, multicentre, single-arm, open-label study .
Lancet Respir Med.
Published on March 26, 2021.
DOI: https://doi.
org/10.
1016/S2213-2600(20)30455-0.
4.
Y.
Shi et al.
, CNS Efficacy of AST2818 in Patients with T790M- Positive Advanced NSCLC:Data from a Phase I-II Dose-Expansion Study, 2020 WCLC, Abstract 3286.
5.
Yuankai Shi, et al.
, Safety, Clinical Activity, and Pharmacokinetics of Alflutinib (AST2818) in Patients With Advanced NSCLC With EGFR T790M Mutation, Journal of Thoracic Oncology, January 2020.
6.
Baohui Han et al.
, Preclinical and Preliminary Clinical Investigations of Furmonertinib in NSCLC with EGFR exon 20 insertions (20ins); 2021 ESMO, Abstract 1325.